Pain is one of the most frequent symptoms for which patients seek medical intervention. Pain may be classified as acute or chronic. Acute pain may be generally associated with excessive noxious stimulus resulting in a severe distressful sensation whereas chronic pain may be associated with physiological changes resulting from tissue or nerve injury leading to hyperalgesia, an increased amount of pain associated with a mild noxious stimulus, or allodynia, a pain induced by a non-noxious stimulus.
Neurogenic pain is a neurological disorder caused by insult to peripheral nerves, resulting in chronic pain and varying combinations of sensory symptoms, including paresthesia, loss of sensation, and even motor weakness. Neurogenic pain may be long-lasting, and may develop days or month following the injury. Often, this type of chronic pain may be observed in diseases affecting the peripheral nervous system, such as nerve compression syndromes, cutaneous sensory neuropathies and polyneuropathies (of which diabetic neuropathy may be the most well-known).
Amongst the various types of chronic pain, understanding and management of neurogenic pain remains a considerably challenging task for researchers and clinicians. Despite the rapid development of neuroscience and the discovery of new pharmaceutical compounds, a need continues to exist for an effective treatment based on a basic understanding of the contributing molecular mechanisms of neurogenic pain.
Neurogenic pain involves alterations in the function of both the peripheral and central nervous system, postulated to be caused by changes in mechano-insensitive peptidergic nociceptors referred to as “silent” or “sleeping” nociceptors, which are chemo-sensitive and respond to noxious chemicals typically released in response to tissue or nerve trauma. Once sensitized, the phenotype of the nociceptors can be altered, whereby the formerly “silent” or “sleeping” nociceptors become “polymodal” or “awake” nociceptors (C fibers), which release significant amounts of pro-inflammatory neuropeptides, such as calcitonin gene-related peptide (CGRP) or substance P (SP), initiating neurogenic inflammation in combination with enhancing action potentials, thereby resulting in increased nociception.
Following nerve injury, increased excitability and sensitivity is observed in the cell body of the injured dorsal root ganglia neurons and neighboring intact afferent neurons. This enhanced stimulation involving the primary afferent neurons is defined as peripheral sensitization, which is mediated by increased expression of the transient receptor potential (TRP) family of non-specific cation channels, including transient receptor potential cation channel subfamily V member 1 (TRPV1), which is expressed in C fibers and Aδ fibers. Another mechanism leading to peripheral sensitization includes the accumulation of voltage-gated sodium channels at the site of the injured nerve and at the dorsal root ganglion, resulting in abnormal ectopic excitability of afferent neurons. These changes may be perceived as spontaneous positive sensations, such as paresthesia (a sensation of tingling, burning, pricking, or numbness of skin) or dysthesia (an unpleasant, abnormal sense of touch).
Central sensitization, defined as the activation of second order nociceptive neurons in the dorsal horn of the spinal cord by peripheral nerve damage, results from the release of glutamate, SP, or other transmitters or cytokines, such as adenosine-5′-triphosphate (ATP), chemokine (C—C motif) ligand 2 (CCL2), or interferon gamma (INFγ), from the central terminals of primary nociceptive afferents in the dorsal horn. The overall effect of these changes may be prolonged excitability of the spinal cord neurons (long-term potentiation).
Further contributing factors to the development of neurogenic pain include the involvement of spinal cord microglia and astrocytes in enhancing pain, whereby ATP-activated microglial P2X4 and P2X7 receptors stimulate the p38 mitogen-activated protein kinases (p38-MAPK) signalling cascade, resulting in release of substances such as brain-derived neurotrophic factor (BNDF), down-regulation of potassium/chloride cotransporters, and diminished inhibitory neurotransmission (GABAergic inhibition).
Additionally, following an injury, various inflammatory substances such as histamines, prostaglandins, or cytokines, may be released from inflammatory cells which have migrated through the blood to the site of the injured tissue. When the injury results in nerve damage, the peripheral terminals of sensory neurons may be activated, resulting in inflammation characterized by the release of neuropeptides, such as CGRP, SP, or calcitonin, from the C fiber terminal, which can lead to vasodilation, edema, or pain. As such, neurogenic inflammation plays an integral role in the pathophysiology of neurogenic pain.
Successful treatment of neurogenic pain requires direct targeting of the receptors and transmitters involved. Conventional therapeutic strategies aim to reduce neuron excitability through alterations in ion channel activity, which may be targeted by compounds such as gabapentin or lidocaine, or modulate central neurotransmission, which may be targeted by compounds such as opioids or tricyclic antidepressants. Despite consistent efficacy observed in randomized trials and meta-analyses, the use of these agents may be limited due to debilitating side effects, such as sedation, somnolence, dry mouth, urinary retention, erythema, ataxia, or the like, or combinations thereof. Moreover, patients using these compounds must be closely monitored and dose tapering may be required to prevent withdrawal symptoms. Accordingly, a need exists for a novel alternative characterized by maximal therapeutic efficacy, minimal toxicity, and low incidence of side effects.